Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides.
(+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.
Vince
R
R
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Hua
M
M
D000818:Animals; D000998:Antiviral Agents; D055598:Chemical Phenomena; D002621:Chemistry; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D016048:Dideoxyadenosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D007941:Leukemia P388 / Q000188:drug therapy; D015394:Molecular Structure; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011684:Purine Nucleosides; C057503:carbovir; D015215:Zidovudine; D016048:Dideoxyadenosine